New therapeutic agents are urgently needed for the treatment of sickle cell disease, the world's most common genetic disease. Our long-term goal is to develop a botanical drug (SCD- 101) for use in children and adults that slows or stops disease progression. Sickle cell disease affects approximately 100,000 people in the United States and millions worldwide. In the US, those with SCD have an average mortality in their 40s and an estimated aggregate cost of medical care in excess of $1.4 billion per year. In less developed countries, 80% of children with SCD die before the age of five. The only FDA approved disease-modifying drug for use in SCD is the anti-cancer drug hydroxyurea, which has serious side effects and is only approved for use in adults. Sickle cell disease results from a mutation in the ?-globin gene (Hb S), a variant of Hb A, the common adult hemoglobin. When deoxygenated, Hb S polymerizes, forming long polymers that deform the biconcave red blood cells (RBCs) into rigid, adherent, sickle-shaped cells. The rigid sickled RBCs are easily trapped in the microvasculature, blocking blood flow to tissues and organs with resultant ischemic tissue damage. Best supportive therapies for SCD include folic acid for anemia, penicillin to prevent infections, pneumococcal and influenza vaccinations, pain medication, and intravenous injection of fluids. Chronic transfusion therapy can modify the course of the disease, but hyperviscosity, alloimmune reaction, infection, and iron overload are just a few of the complications of transfusion therapy. Bone marrow transplants can cure SCD, but the morbidity and mortality of the procedure, coupled with difficulty in finding a donor match and the cost of the procedure, leave this an uncommon treatment option. SCD-101 is being evaluated in a Phase 1B dose escalation trial in adults with sickle cell disease to obtain an initial safety profile and explore possible effective oral doses that inhibit RBCs from sickling. Early data shows that SCD-101 can inhibit RBC sickling in humans. To proceed to a Phase II clinical trial additional non-clinical studies are needed. This Phase II grant proposal is for funding the necessary non-clinical studies.